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A 3d cell culture model of the tuberculosis granuloma that can be applied for h...

David, Susana; Mandal, Manoj; Anes, Elsa; Pires, David

Introduction: The granuloma is an inflammatory infiltrate of mononuclear cells. Some bacterial infections are characterized by the formation of granulomas as part of the immune response to contain the infection. Granuloma models have contributed valuable insights into the genetic basis of granuloma formation during infection. For example, IFNGR1 and IFNGR2 variants have been found to disrupt the immune response...


Host-directed therapies based on protease inhibitors to control Mycobacterium t...

Mandal, Manoj; Pires, David; Azevedo-Pereira, Jose Miguel; Anes, Elsa

Despite continuous and extensive global efforts in the fight against tuberculosis (TB), this infectious disease continues to exert a tremendous burden on public health concerns and deaths worldwide. TB, caused by the bacterial species Mycobacterium tuberculosis, is highly frequent in people living with HIV. The continuing epidemics of both chronic infections and the emergence of antimicrobial resistance, as wel...


Cystatin F depletion in Mycobacterium tuberculosis-infected macrophages improve...

Mandal, Manoj; Pires, David; Calado, Marta; Azevedo-Pereira, Jose Miguel; Anes, Elsa

Cystatin F (CstF) is a protease inhibitor of cysteine cathepsins, including those involved in activating the perforin/granzyme cytotoxic pathways. It is targeted at the endolysosomal pathway but can also be secreted to the extracellular milieu or endocytosed by bystander cells. CstF was shown to be significantly increased in tuberculous pleurisy, and during HIV coinfection, pleural fluids display high viral loa...


ESAT-6 a major virulence factor of mycobacterium tuberculosis

Anes, Elsa; Pires, David; Mandal, Manoj; Azevedo-Pereira, José Miguel

Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis (TB), is one of the most successfully adapted human pathogens. Human-to-human transmission occurs at high rates through aerosols containing bacteria, but the pathogen evolved prior to the establishment of crowded populations. Mtb has developed a particular strategy to ensure persistence in the host until an opportunity for transmission ...



Development of chitosan particles loaded with siRNA for cystatin C to control i...

Pires, David; Mandal, Manoj; Matos, Ana I.; Peres, Carina; Catalão, Maria João; Azevedo-Pereira, José Miguel; Satchi-Fainaro, Ronit; Florindo, Helena F.

The golden age of antibiotics for tuberculosis (TB) is marked by its success in the 1950s of the last century. However, TB is not under control, and the rise in antibiotic resistance worldwide is a major threat to global health care. Understanding the complex interactions between TB bacilli and their host can inform the rational design of better TB therapeutics, including vaccines, new antibiotics, and host-dir...


HIV/Mtb co-infection: from the amplification of disease pathogenesis to an "eme...

Azevedo-Pereira, José Miguel; Pires, David; Calado, Marta; Mandal, Manoj; Santos-Costa, Quirina; Anes, Elsa

Human immunodeficiency virus (HIV) and Mycobacterium tuberculosis (Mtb) are pathogens responsible for millions of new infections each year; together, they cause high morbidity and mortality worldwide. In addition, late-stage HIV infection increases the risk of developing tuberculosis (TB) by a factor of 20 in latently infected people, and even patients with controlled HIV infection on antiretroviral therapy (AR...


Liposomal delivery of repurposed antiviral drug saquinavir to macrophages as a ...

Mandal, Manoj; Pires, David; Pinho, Jacinta; Catalão, Maria João; Almeida, António José; Azevedo-Pereira, José Miguel; Gaspar, Maria Manuela; Anes, Elsa

Mycobacterium tuberculosis (Mtb) latently infects approximately a quarter of the world’s population and 10 % of these will develop the disease tuberculosis. Mtb infects macrophages, manipulating the proteolytic mechanisms, particularly, by decreasing the expression and activity of lysosomal cathepsins. Consequently, Mtb survives and even replicates inside macrophages concomitant with poor priming of the adaptiv...


Development and characterisation of a 3D cell culture model of the tuberculosis...

Pires, David; David, Susana; Mandal, Manoj; Soderberg, Julia; Anes, Elsa

Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis (Mtb) that results in 1.6 million deaths yearly. The TB granuloma is the hallmark cellular structure of latent TB that contains the spread of infection1 . More comprehensive in vitro models of TB that better resemble the cellular and immunoregulatory complexity of the granuloma would facilitate the study of the interplay between the bacteria an...


Modulation of cystatin f in human macrophages impacts cathepsin-driven killing ...

Mandal, Manoj; Pires, David; Catalão, Maria João; Azevedo-Pereira, José Miguel; Anes, Elsa

Tuberculosis (TB) treatment relies primarily on 70-year-old drugs, and prophylaxis suffers from the lack of an effective vaccine. Among the 10 million people exhibiting disease symptoms yearly, 450,000 have multidrug or extensively drug-resistant (MDR or XDR) TB. A greater understanding of host and pathogen interactions will lead to new therapeutic interventions for TB eradication. One of the strategies will be...


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